Overview

Benefits From Finasteride and Dutasteride Chemoprevention

Chemoprevention with finasteride and dutasteride reduces the incidence of prostate cancer, but the evidence is inadequate to determine whether chemoprevention with finasteride or dutasteride reduces mortality from prostate cancer.

Magnitude of Effect: Absolute reduction in incidence for more than 7 years with finasteride was 6% (24.4% with placebo and 18.4% with finasteride); relative risk reduction (RRR) for incidence was 24.8% (95% confidence interval [CI], 18.6%–30.6%). There was no difference in the number of men dying from prostate cancer in the two groups, though the number of deaths was small.

In the dutasteride trial, using the restricted crude rate absolute risk reduction was 5.1% at 4 years, and RRR was 22.8% (95% CI, 15.2%–29.8%, P < .001). There was no difference in prostate cancer or overall mortality, though the number of deaths was small and none were due to prostate cancer. The reduction in prostate cancer incidence occurred primarily in Gleason 5 to 6 cancers.[1] The reduction in incidence primarily in less aggressive cancers (i.e., Gleason 5–6) and not in more aggressive cancers (i.e., Gleason 7–10) raises the question of whether this reduction in incidence would lead to any reduction in mortality. This question is presently unanswered.

Study Design: Two randomized controlled trials; one for finasteride and one for dutasteride.

Internal Validity: Good for the outcome of incidence, poor for the outcome of mortality.

Consistency: Good.

External Validity: The studies focused on different populations. The finasteride trial enrolled men with a prostate-specific antigen (PSA) of more than 3 ng/mL, constituting the majority of U.S. men, but men with a lower risk of cancer. In the dutasteride trial, men were at somewhat higher risk, with a PSA of 2.5 to 10.0 and a prior negative biopsy. As such, results are generalizable primarily to these respective populations.

Harms From Finasteride and Dutasteride Chemoprevention

Finasteride

Men in the finasteride group had statistically significantly more erectile dysfunction, loss of libido, and gynecomastia than men in the placebo group. Men in the finasteride group had a statistically significant incidence of high-grade (Gleason sum 8–10) cancers during the study.[2]

Magnitude of Effect: Statistically significant increases in the following outcomes were observed in the finasteride group (a greater fraction of men in the finasteride group [36.8%] temporarily discontinued treatment at some time during the study for reasons other than death or a diagnosis of prostate cancer than in the placebo group [28.9%]):

Percentage in finasteride group versus percentage in placebo group:

Reduced volume of ejaculate (60.4% vs. 47.3%).

Erectile dysfunction (67.4% vs. 61.5%).

Loss of libido (65.4% vs. 59.6%).

Gynecomastia (4.5% vs. 2.8%).

Dutasteride

Overall, 4.3% of men in the dutasteride group compared with 2% of men in the placebo group discontinued the trial because of drug-related adverse events (P < .001). Men in the dutasteride group had a higher incidence of decreased libido, loss of libido, decreased semen volume, erectile dysfunction, and gynecomastia than men in the placebo group.[1]

Magnitude of Effect: Increases in the following outcomes were observed in the dutasteride group:

Percentage in dutasteride group versus percentage in placebo group:

Decreased libido (3.3% vs. 1.6%).

Loss of libido (1.9% vs. 1.3%).

Decreased semen volume (1.4% vs. 0.2%).

Erectile dysfunction (9.0% vs. 5.7%).

Gynecomastia (1.9% vs. 1.0%).

Study Design: Two randomized controlled trials; one for finasteride and one for dutasteride.

Internal Validity: Good: The finasteride trial used two subject-completed sexual functioning instruments administered at enrollment, randomization, 6 months, and annually over the 7-year study. The dutasteride trial administered a sexual functioning instrument after completion of placebo run-in and annually thereafter.

Consistency: Good (evidence other than the randomized controlled trial supports these effects).

External Validity: As above, the studies evaluated two different populations: PSA less than or equal to 3 ng/mL in the finasteride trial and PSA of 2.5 to 10.0 ng/mL with a prior negative biopsy in the REDUCE trial. The results are most generalizable to these two populations.

U.S. Food and Drug Administration (FDA) Review of Finasteride and Dutasteride

The Oncology Drugs Advisory Committee of the FDA examined both finasteride and dutasteride in 2010. Neither agent was recommended for use for chemoprevention of prostate cancer.

Magnitude of Effect: Compared with the placebo group in which 529 men developed prostate cancer, there was a statistically significant increase in prostate cancer in the vitamin E group (620 cases) but not in the selenium plus vitamin E group (555 cases) or in the selenium group (575 cases). The magnitude of increase in prostate cancer risk with vitamin E alone was 17%.

Significance

Incidence and Mortality

Carcinoma of the prostate is the most common tumor in men in the United States (other than skin cancer),
with an estimated 161,360 new cases and 26,730 deaths expected in 2017.[1] A wide range of
estimates of the impact of the disease are notable. The disease is
histologically evident in as many as 34% of men in their fifth decade and in up
to 70% of men aged 80 years and older.[2,3] Prostate cancer will be
diagnosed in almost one-fifth of U.S. men compared with about 3% of
men who will be expected to die of the disease.[4] The estimated reduction in life
expectancy of men who die of prostate cancer is approximately 9 years.[5]

The extraordinarily high rate of clinically occult prostate cancer in the
general population compared with the 20-fold lower likelihood of death from the
disease indicates that many of these cancers have low biologic risk. Concordant
with this observation are the many series of patients with lower-risk (i.e., Gleason 6 and some low-volume Gleason 7 tumors) prostate cancer
managed by surveillance alone with high survival rates at 5 and 10
years of follow-up.[6] Data demonstrate, however, that with longer follow-up, higher-grade cancers are associated with a greater risk of prostate cancer death.[7,8]

Because of marked variability in tumor differentiation from one microscopic field to another, many pathologists will report the range of differentiation among the malignant cells that are present in a biopsy using the Gleason grading system. This grading system includes five histologic patterns distinguished by the glandular architecture of the cancer. The architectural patterns are identified and assigned a grade from 1 to 5 with 1 being the most differentiated and 5 being the least differentiated. The sum of the grades of the predominant and next most prevalent will range from 2 (well-differentiated tumors) to 10 (undifferentiated tumors).[9,10] Systematic changes to the histological interpretation of biopsy specimens by anatomical pathologists have occurred during the prostate-specific antigen (PSA) screening era (i.e., since about 1985) in the United States.[11] This phenomenon, sometimes called “grade inflation,” is the apparent increase in the distribution of high-grade tumors in the population for a period of time but in the absence of a true biological or clinical change. It is possibly the result of an increasing tendency for pathologists to read tumor grade as more aggressive, resulting in a higher preponderance to treat these cancers aggressively.[12]

Treatment options available for prostate cancer include radical prostatectomy,
external-beam radiation therapy, brachytherapy, cryotherapy, focal ablation, androgen deprivation with luteinizing hormone-releasing hormone analogs and/or antiandrogens, intermittent androgen deprivation, cytotoxic agents, and active surveillance. Of all the means of management, only radical prostatectomy has been tested in a randomized clinical trial to assess survival benefit. In this study, prostatectomy was found to be superior to surveillance in men with localized prostate cancer in terms of reduced rates of metastases (relative hazard [RH] = 0.63; 95% confidence interval [CI], 0.41–0.96) and disease specific (RH = 0.5; 95% CI, 0.27–0.91) and overall mortalities.[13] The relative efficacy of radical prostatectomy to the other forms of treatment has not been adequately addressed.[14] Confounding issues in the treatment of prostate cancer include side
effects with treatment, inability to predict the natural history of a given
cancer, patient comorbidity that may affect an individual’s likelihood of
surviving long enough to be at risk for disease morbidity and mortality, and an increasing body of evidence suggesting that with careful PSA monitoring following treatment, a
substantial fraction of patients may suffer disease recurrence.[15]

Because of considerable uncertainty regarding the efficacy of treatment and the
difficulty with selecting patients for whom there is a known risk of disease
progression, opinion in the medical community is divided regarding
screening for carcinoma of the prostate. While both digital rectal examination
and PSA screening have demonstrated reasonable performance characteristics (sensitivity,
specificity, and positive predictive value) for the early detection of prostate
cancer, conflicting outcomes of randomized trials examining the impact of screening on mortality has led to some organizations to recommend for and others to recommend against screening.[16,17]

The tremendous impact of prostate cancer on the U.S. population and the
financial burden of the disease for both patients and society have led to an
increased interest in primary disease prevention.

Risk Factors for Prostate Cancer Development

Age

Prostate cancer incidence escalates dramatically
with increasing age. Although it is a very unusual disease in men younger than 50 years, rates
increase exponentially thereafter. The registration rate by age cohort in
England and Wales increased from eight per thousand population in men aged 50 to 56 years to
68 per thousand in men aged 60 to 64 years; 260 per thousand in men aged 70 to 74 years, and
peaked at 406 per thousand in men aged 75 to 79 years.[1] In this same population, the death rate per thousand
in 1992 in cohorts of men aged 50 to 54 years, 60 to 64 years, and 70 to 74 years was 4, 37, and 166, respectively.[1] At all ages, incidence of
prostate cancer in blacks exceeds those of whites.[2]

Family History

Approximately 15% of men with a diagnosis of prostate cancer will be found to
have a first-degree male relative (e.g., brother, father) with prostate cancer,
compared with approximately 8% of the U.S. population.[3] Approximately 9% of all prostate cancers may result from heritable
susceptibility genes.[4] Several authors have completed segregation analyses,
and though a single, rare autosomal gene has been suggested to cause cancer
in some of these families, the burden of evidence suggests that the inheritance
is considerably more complex.[5-7]

Hormones

The development of the prostate is dependent upon the secretion of dihydrotestosterone (DHT)
by the fetal testis. Testosterone causes normal virilization of the Wolffian
duct structures and internal genitalia and is acted upon by the enzyme 5-alpha-reductase (5AR) to form DHT. DHT has a 4-fold to 50-fold greater affinity for the androgen receptor than testosterone, and it is
DHT that leads to normal prostatic development. Children born with abnormal
5AR (due to a change in a single base pair in exon 5 of the normal type II 5AR
gene), are born with ambiguous genitalia (variously described as hypospadias
with a blind-ending vagina to a small phallus) but masculinize at puberty because of the surge of testosterone production at that time. Clinical, imaging, and
histologic studies of kindreds born with 5AR deficiency have demonstrated a
small, pancake-appearing prostate with an undetectable prostate-specific
antigen (PSA) level and no evidence of prostatic epithelium.[8] Long-term follow-up
demonstrates that neither benign prostatic hyperplasia (BPH) nor prostate
cancer develop.

Other evidence suggesting that the degree of cumulative exposure of the
prostate to androgens is related to an increased risk of prostate cancer
includes the following:

Neither BPH nor prostate cancer have been reported in men castrated
prior to puberty.[9]

Androgen deprivation in almost all forms leads to involution of the
prostate, a fall in PSA levels, apoptosis of prostate cancer and
epithelial cells, and a clinical response in prostate cancer
patients.[10,11]

The results of two large-scale chemoprevention trials using 5AR inhibitors (finasteride and dutasteride) demonstrate that intraprostatic androgens modulate prostate cancer risk. In both studies, reductions in overall prostate cancer risk were identified although with increased risk of high-grade disease.[12,13]

Ecological studies have found a correlation between serum levels of testosterone, especially DHT, and overall risk of prostate cancer among African American, white, and Japanese males.[14-16] However, evidence from prospective studies of the association between serum concentrations of sex hormones, including androgens and estrogens, does not support a direct link.[17] A collaborative analysis of 18 prospective studies, pooling prediagnostic measures on 3,886 men with incident prostate cancer and 6,438 control subjects, found no association between the risk of prostate cancer and serum concentrations of testosterone, calculated-free testosterone, dihydrotestosterone sulfate, androstenedione, androstanediol glucuronide, estradiol, or calculated-free estradiol.[17] A caution for interpreting the data is the unknown degree of correlation between serum levels and prostate tissue level. Androstanediol glucuronide may most closely reflect intraprostatic androgen activity, and this measure was not associated with the risk of prostate cancer. This lack of association affirms that risk stratification cannot be made on serum hormone concentrations.

Race

The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of
intermediate levels among whites, and is lowest among native Japanese.[18,19] Conflicting data have been published regarding
the etiology of these outcomes, but some evidence is available that access to
health care may play a role in disease outcomes.[20]

Dietary Fat

An interesting observation is that although the incidence of latent (occult,
histologically evident) prostate cancer is similar throughout the world,
clinical prostate cancer varies from country to country by as much as 20-fold.[21] Previous ecologic studies have demonstrated a direct relationship
between a country’s prostate cancer-specific mortality rate and average total
calories from fat consumed by the country’s population.[22,23] Studies of
immigrants from Japan have demonstrated that native Japanese have the lowest
risk of clinical prostate cancer, first generation Japanese-Americans have an
intermediate risk, and subsequent generations have a risk comparable to the
U.S. population.[24,25] Animal models of explanted human prostate cancer have
demonstrated decreased tumor growth rates in animals who are fed a low-fat diet.[26,27]
Evidence from many case-control studies has found an association
between dietary fat and prostate cancer risk,[28-30] though studies have not
uniformly reached this conclusion.[31-33] In a review of published studies of
the relationship between dietary fat and prostate cancer risk, among
descriptive studies, approximately half found an increased risk with increased
dietary fat and half found no association.[34] Among case-control studies,
about half of the studies found an increased risk with increasing
dietary fat, animal fat, and saturated and monounsaturated fat intake while
approximately half found no association. Only in studies of polyunsaturated
fat intake were three studies reported of a significant negative association
between prostate cancer and fat intake. Fat of animal origin seems
to be associated with the highest risk.[20,35] In a series of 384 patients
with prostate cancer, the risk of cancer progression to an advanced stage was
greater in men with a high fat intake.[36] The announcement in 1996 that
cancer mortality rates had fallen in the United States prompted the suggestion
that this may be caused by decreases in dietary fat intake during the same time
period.[37,38]

Two studies were conducted within the Prostate Cancer Prevention Trial in which prospective nutritional information was collected and all subjects were recommended to undergo biopsy. Findings included that, among 9,559 subjects there was no association between any supplement or nutrient (including fat) and risk of prostate cancer overall but the risk of high-grade cancer was associated with high intake of polyunsaturated fats. In a subset of 1,658 cases and 1,803 controls, specific fatty acids were examined and docosahexaenoic acid was associated with risk of high-grade disease while trans-fatty acids (TFA) 18:1 and TFA 18:2 were inversely associated with risk of high-grade disease. These large scale studies suggest a complex relationship between nutrients such as fat and risk of prostate cancer.[39,40]

The explanation for this possible association between prostate cancer and
dietary fat is unknown. Several hypotheses have been advanced, including:

Dietary fat may increase serum androgen levels, thereby increasing
prostate cancer risk. This hypothesis is supported by observations
from South Africa and the United States that changes in dietary fat
intake change urinary and serum levels of androgens.[41,42]

Certain types of fatty acids or their metabolites may initiate or
promote prostate carcinoma development. The evidence for this
hypothesis is conflicting, but one study suggests that linoleic acid
(omega-6 polyunsaturated fatty acid) may stimulate prostate cancer
cells, while omega-3 fatty acids inhibit cell growth.[43]

An observation made in an animal model is that male offspring of
pregnant rats who are fed a high-fat diet will develop prostate cancer at a
higher rate than animals who are fed a low-fat diet.[44] This observation may
explain some of the variations in prostate cancer incidence and
mortality among ethnic groups; an observation has been made that
first trimester androgen levels in pregnant blacks are higher than
those in whites.[45]

Dairy and Calcium Intake

In a meta-analysis of ten cohort studies (eight from the United States and two from Europe), it was concluded that men with the highest intake of dairy products (relative risk [RR] = 1.11; 95% confidence interval [CI], 1.00–1.22; P = .04) and calcium (RR = 1.39; 95% CI, 1.09–1.77; P = .18) were more likely to develop prostate cancer than men with the lowest intake. The pooled RRs of advanced prostate cancer were 1.33 (95% CI, 1.00–1.78; P = .055) for the highest versus lowest intake categories of dairy products and 1.46 (95% CI, 0.65–3.25; P > .2) for the highest versus lowest intake categories of calcium. High intake of dairy products and calcium may be associated with an increased risk of prostate cancer although the increase may be small.[46]

Multivitamin Use

Regular multivitamin use has not been associated with the risk of early or localized prostate cancer. However, in this large (295,344 men) study, there was a statistically significantly increased risk of advanced and fatal prostate cancer among men with excessive use of multivitamins.[47]

Folate

The Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas, was conducted between July 6, 1994, and December 31, 2006. In a secondary analysis, the authors addressed the effect of folic acid supplementation on the risk of prostate cancer. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0–7.8) years and asked periodically to report all illnesses and hospitalizations.[48] Supplementation with 1 mg of folic acid was associated with an increased risk of prostate cancer. However, dietary and plasma levels among nonmultivitamin users were inversely associated with risk. These findings highlight the potentially complex role of folate in prostate carcinogenesis.[48,49]

Cadmium Exposure

Cadmium exposure is occupationally associated with nickel-cadmium
batteries and cadmium recovery plant smelters and is associated with
cigarette smoke.[50] The earliest studies of this agent documented an apparent association, but better-designed studies have failed to note an
association.[51,52]

Dioxin Exposure

Dioxin (2,3,7,8 tetrachlorodibenzo-p-dioxin or TCDD) is a contaminant of an
herbicide used in Vietnam. This agent is similar to many components of
herbicides used in farming. A review of the linkage between dioxin and
prostate cancer risk by the National Academy of Sciences Institute of Medicine
Committee to Review the Health Effects in Vietnam Veterans of Exposure to
Herbicides, found only two articles on prostate cancer with sufficient
numbers of cases and follow-up to allow analysis.[53,54] The analysis of all
available data suggests that the association between dioxin exposure and
prostate cancer is not conclusive.[55]

Opportunities for Prevention

Hormonal Prevention

The Prostate Cancer Prevention Trial (PCPT), a large randomized placebo-controlled trial of finasteride (an inhibitor of alpha-reductase), was performed in 18,882 men aged 55 years or older. At 7 years, the incidence of prostate cancer was 18.4% in the finasteride group versus 24.4% in the placebo group, a relative risk reduction (RRR) of 24.8% (95% confidence interval [CI], 18.6%–30.6%; P < .001). The finasteride group had more patients with Gleason grade 7 to 10, but the clinical significance of Gleason scoring is uncertain in conditions of androgen deprivation.[1]
High-grade cancers were noted in 6.4% of finasteride patients, compared with 5.1% of men receiving a placebo. The increase in high-grade tumors was seen within 1 year of finasteride exposure and did not increase during this time period.[2]

Finasteride decreases the risk of prostate cancer but may also alter
the detection of disease through effects on prostate-specific antigen (PSA), prostate digital rectal examination,
and decreased prostate volume (24%), creating a detection bias.[3] Adjustment of PSA in men taking finasteride preserves the performance characteristics for cancer detection.[4]

It is possible that finasteride induced the development of high-grade epithelial neoplasia, but this has not been demonstrated.[3] With a finasteride-induced development of high-grade prostate cancer, a gradual and progressive increase in the number of high-grade tumors would have been expected for more than 7 years, compared with placebo; however, this was not the case. The increase in high-grade tumors was seen within 1 year of finasteride exposure and did not increase during this time period.[2] An analysis of the PCPT data adjusted for the sources of detection bias found that finasteride reduced the incidence of Gleason 5 to 7 and Gleason 3 to 4 prostate cancer, but not Gleason 2 to 3 or Gleason 8 to 10. The reduction in the incidence of Gleason 7 (22%) was less than the reduction in the incidence of Gleason 5 (58%) and Gleason 6 (52%).[5] An analysis using different methodologies found an overall reduction of both low-grade (Gleason <6) and high-grade (Gleason >7) cancers.[6]

The Reduction by Dutasteride of Prostate Cancer Events trial randomly assigned 8,231 men aged 50 to 75 years at higher risk of prostate cancer (i.e., PSA 2.5–10.0) with one recent negative prostate biopsy to dutasteride at 0.5 mg daily or to placebo. The primary endpoint was prostate cancer diagnosed by prostate biopsy at 2 years and 4 years after randomization. After 4 years, among the 6,729 men (82% of initial population) who had at least one prostate biopsy, 25.1% of the placebo group and 19.9% of the dutasteride group had been diagnosed with prostate cancer, a statistically significant difference (absolute risk reduction = 5.1% and RRR = 22.8% [95% CI, 15.2%–29.8%]). The RRR in years 3 to 4 was similar to the RRR in years 1 to 2. The difference between the groups was entirely due to a reduction in prostate cancers with Gleason score 5 to 7. For years 3 to 4 there was a statistically significant increase in the dutasteride group compared with the placebo group in prostate cancers with Gleason score 8 to 10 (12 cancers in dutasteride group vs. 1 cancer in placebo group).[7]

Overall, there was no statistically significant difference of high-grade tumors for Gleason 8 to 10 cancers in years 1 to 4 (29 tumors in the dutasteride group vs. 19 tumors in the placebo group, 0.9% vs. 0.6%; P = .15). However, in a retrospective analysis there was a statistically significant difference between years 3 to 4. Because this is a small retrospective subgroup, the finding of an increase in Gleason 8 to 10 cancers is of uncertain validity. However, the finding of no reduction in these cancers is more significant.[7]

There are several plausible explanations for the failure of finasteride or dutasteride to reduce the incidence of Gleason 8 to 10 cancers. Because of this uncertainty, the evidence is currently insufficient to determine the effect of prophylaxis with these drugs on prostate cancer mortality.

Agents that are used
for hormonal therapy of existing prostate cancers would be unsuitable for
prostate cancer chemoprevention because of the cost and wide variety of side
effects including sexual dysfunction, osteoporosis, and vasomotor symptoms (hot
flushes).[8] Newer antiandrogens may play a role
as preventive agents in the future.[9]

A Cochrane systematic review of all published studies of clinical outcome investigations of the prostate preventive effects of 5-alpha-reductase (5AR) inhibitors through 2010 that were at least one year in duration concluded that finasteride and dutasteride reduce the risk of being diagnosed with prostate among men who are screened regularly for prostate cancer. The review also concluded that mortality effects could not be assessed from these studies and that persistent use of these agents increased sexual and erectile dysfunction. The review was based on MEDLINE and Cochrane Collaboration Library computerized searches through June 2010 using the Medical Subject Headings terms and text words finasteride, dutasteride, neoplasms, azasteroids, reductase inhibitors, and enzyme inhibitors to identify randomized trials. Eight studies met the inclusion criteria. Only the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events study were designed to assess the impact of 5AR inhibitors on prostate cancer period prevalence. Reviews of all eight studies concluded that compared with placebo, 5AR inhibitors resulted in 25% relative risk (RR) reduction in prostate cancers detected for cause (RR, 0.75; 95% CI, 0.67–0.83 and 1.4% absolute risk reduction [3.5% vs. 4.9%]). Six trials of 5AR inhibitors versus placebo assessed prostate cancers detected overall. Among these there was a 26% RR reduction favoring 5AR inhibitors (RR, 0.74; 95% CI, 0.55–1.00 and 2.9% absolute risk reduction [6.3% vs. 9.2%]). There were reductions across age, race, and family history. One placebo-controlled trial of men considered at greater risk for prostate cancer based on age, elevated PSA, and previous suspicion of prostate cancer leading to a prostate biopsy reported that dutasteride did not reduce prostate cancers detected for cause based on needle biopsy but did reduce risk of overall incident prostate cancer detected by biopsy by 23% (RR, 0.77; 95% CI, 0.7–0.85 and absolute risk reduction, 16.1% vs. 20.8%). There were reductions across age, family history of prostate cancer, PSA level, and prostate volume subgroups. The Cochrane review defined "for cause" cancers as:

Study protocol recommended biopsy, but it was not done and the end of study biopsy showed prostate cancer.

The end of study biopsy with PSA less than 4 ng/mL and/or suspicious DRE showed prostate cancer.[10]

Dietary Prevention With Fruit, Vegetables, and a Low-fat Diet

Results from studies of the association between dietary intake of fruits and vegetables and risk of prostate cancer are not consistent. A study evaluated 1,619
prostate cancer cases and 1,618 controls in a multicenter, multiethnic
population. The study found that intake of legumes and yellow-orange and
cruciferous vegetables was associated with a lower risk of prostate cancer.

The European Prospective Investigation into Cancer and Nutrition examined the association between fruit and vegetable intake and subsequent prostate cancer. After an average follow-up of 4.8 years, 1,104 men developed prostate cancer among the 130,544 male participants. No statistically significant associations were observed for fruit intake, vegetable intake, cruciferous vegetable intake, or the intake of fruits and vegetables combined.[11]

One study of dietary intervention over a 4-year period with reduced fat and increased consumption of fruit, vegetables, and fiber had no impact on serum PSA levels.[12] It is unknown whether dietary modification through the use of a low-fat, plant-based diet will reduce prostate cancer risk. While this outcome is unknown,
multiple additional benefits may be gleaned by such a diet, to include a lower
risk of hyperlipidemia, better control of blood pressure, and a lower risk of
cardiovascular disease—all of which may merit adoption of such a diet.

Chemoprevention

While several agents, including alpha-tocopherol, selenium, lycopene,
difluoromethylornithine,[13-17] vitamin D,[18-20] and isoflavonoids,[21,22]
have shown potential in either clinical or laboratory studies for
chemoprevention of prostate cancer, the correlations of cancer prevention with these agents are increasingly of concern given the statistically increased risk of prostate cancer with alpha-tocopherol in the SELECT trial and the lack of preventive effect (actually, a non-significant increase in prostate cancer risk) with selenium.

Chemoprevention with selenium and vitamin E

The Selenium and Vitamin E Cancer Prevention Trial (SELECT [NCT00006392]) was a large randomized placebo-controlled trial of vitamin E and selenium. It showed no reduction in prostate cancer period prevalence, but an increased risk of prostate cancer with vitamin E alone.[23]

Compared with the placebo group in which 529 men developed prostate cancer, there was a statistically significant increase in prostate cancer in the vitamin E group (620 cases), but not in the selenium plus vitamin E group (555 cases) or in the selenium group (575 cases). The magnitude of increase in prostate cancer risk with vitamin E alone was 17%. Of interest, the statistically increased risk of prostate cancer among men receiving vitamin E was seen after study supplements had been discontinued suggesting a prolonged effect of this agent.[23]

Chemoprevention with lycopene

Evidence exists that a diet with a high intake of fruits and vegetables is
associated with a lower risk of cancer. Which, if any, micronutrients may
account for this reduction is unknown. One group of nutrients often postulated
as having chemoprevention properties is the carotenoids. Lycopene is the
predominant circulating carotenoid in Americans and has a number of potential
activities, including an antioxidant effect.[24] It is encountered in a number
of vegetables, most notably tomatoes, and is best absorbed if these products
are cooked and in the presence of dietary fats or oils.

The earliest studies of the association of lycopene and prostate cancer risk
were generally negative before 1995 with only one study of 180 case-control patients
showing a reduced risk.[25-28] In 1995, an analysis of the Physicians’
Health Study found a one-third reduction in prostate cancer risk in the group
of men with the highest consumption of tomato products when compared with the group
with the lowest level of consumption, which was attributed to the lycopene
content of these vegetables.[29] This large analysis prompted several
subsequent studies, the results of which were mixed.[30,31] A review of the
published data concluded that the evidence is weak that lycopene is associated
with a reduced risk because previous studies were not controlled for total
vegetable intake (i.e., separating the effect of tomatoes from vegetables), dietary intake instruments are poorly able to quantify lycopene
intake, and other potential biases.[32] Specific dietary supplementation with
lycopene remains to be demonstrated to reduce prostate cancer risk. In the largest prospective study to date, the Prostate Cancer Prevention Trial, lycopene was not associated with any reduction in risk of prostate cancer among 9,559 men studied. Similarly, there was no relationship between lycopene serum concentrations and risk of prostate cancer.[33,34]

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about prostate cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Updated: March
17, 2017

Most text on the National Cancer Institute website may be reproduced or reused freely. The National Cancer Institute should be credited as the source and a link to this page included, e.g., “Prostate Cancer Prevention (PDQ®)–Health Professional Version was originally published by the National Cancer Institute.”

Please note that blog posts that are written by individuals from outside the government may be owned by the writer, and graphics may be owned by their creator. In such cases, it is necessary to contact the writer, artists, or publisher to obtain permission for reuse.

We welcome your comments on this post. All comments must follow our comment policy.